Descrizione del progetto
Scoprire i fattori microbici scatenanti delle malattie infiammatorie croniche intestinali
Le malattie infiammatorie croniche intestinali (MICI) sono un gruppo di patologie infiammatorie croniche dell’apparato digerente che colpisce milioni di persone in tutto il mondo. I due tipi principali di MICI sono il morbo di Crohn e la colite ulcerosa. Sempre più prove indicano che le risposte immunitarie anomale al microbiota intestinale possono essere la causa di fondo dell’infiammazione che porta alle MICI. Il progetto IMMUNOBIOME, finanziato dal Consiglio europeo della ricerca, propone una strategia rivoluzionaria per scoprire i bersagli microbici della risposta immunitaria nelle MICI. I ricercatori impiegheranno approcci innovativi per identificare i microbi che vengono presi di mira dalla risposta immunitaria nei pazienti affetti da MICI, fornendo importanti informazioni sul meccanismo di queste malattie.
Obiettivo
The inflammatory bowel diseases (IBD) Crohn’s disease and ulcerative colitis manifest at the host-microbiota interface. The recently revealed genetic underpinning of IBD points towards an aberrant immune response to the intestinal microbiota. The prediction of genetically-impaired microbial handling is exemplified by key risk genes overlapping between leprosy, an infectious disease, and Crohn’s disease. A vigorous search for microbial triggers of IBD, which could also help explain the rising incidence and prevalence of this debilitating condition throughout the world, via high-throughput sequencing studies have indeed revealed structural alterations of the microbiota (‘dysbiosis’) compared to healthy individuals, although it is methodologically impossible to resolve cause-effect relationships of these associations.
Here we propose a two-tier strategy to overcome these limitations of current methods to uncover the microbial targets of the ‘inappropriate’ immune response that characterises IBD. The first tier is based on an entirely novel, and potentially disruptive, method (termed MiIP-Seq - Microbial Immunoprecipitation and Sequencing) that we have developed. MiIP-Seq allows directed metagenomic sequencing of microbes complexed with immunoglobulins in patients with IBD, and hence the identification of those microbes within the microbiota that are targeted by the pathological IgG immune response; induction of massive mucosal IgG exceeding IgA that prevails in health is a core characteristic of IBD. The second tier builds on transfer of the microbiota from patients with active IBD harbouring dominant IBD risk genes into mice genetically hypomorphic at the orthologues of these risk genes, and to resolve the hierarchy of immunologically targeted microbes within the humanised microbiota via MiIP-Seq.
Hence, via exploiting the lens of the immune system and harnessing genetic insight, this study will unravel the ‘environmental, microbial’ triggers and perpetuators of IBD.
Campo scientifico
- natural sciencesbiological sciencesmicrobiologybacteriology
- medical and health sciencesclinical medicinegastroenterologyinflammatory bowel disease
- medical and health scienceshealth sciencesinfectious diseases
- medical and health sciencesbasic medicineimmunology
- natural sciencesbiological sciencesgeneticsgenomes
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
CB2 1TN Cambridge
Regno Unito